Bi-aromatic esters, a process for their preparation and their use in human or veterinary medicine and in cosmetic compositions

ABSTRACT

Bi-aromatic esters have the formula ##STR1## wherein R 1  represents H, OH, --CH 3 , --CH 2  OH, --CH(OH)CH 3 , --COOR 9 , ##STR2## or SO 2  R 10  ; R 9  represents H, C 1  -C 6  alkyl or mono 
     or polyhydroxyalkyl; R 10  represents OH, C 1  -C 6  alkyl or ##STR3## r&#39; and r&#34; represent H, C 1  -C 6  alkyl, aryl, aralkyl, mono or polyhydroxyalkyl, or r&#39; and r&#34; taken together form a heterocycle; R 2  represents H, C 1  -C 6  alkyl, OR 9 , F or --CF 3  ; R 3 , R 4  and R 5  represent H, F, OH, --CH 3 , --OCH 3 , --CF 3 , --COOH or --CH 2  OH; R 6  and R 8  represent H, α-substituted C 3  -C 15  alkyl, α,α&#39;-disubstituted C 4  -C 12  alkyl, C 3  -C 12  cycloalkyl, C 5  -C 12  mono or polycyclic cycloalkyl whose linking carbon is trisubstituted, --SR 11 , --SO 2  R 11  or --SOR 11  ; R 11  represents C 1  -C 6  alkyl or cycloalkyl; R 6  and R 8  cannot simultaneously represent H; R 7  represents H, C 1  -C 6  alkyl, alkenyl, alkenyloxy, OR 12  or SR 13  ; R 12  represents H, C 1  -C 6  alkyl or alkenyl; R 3  represents H, C 1  -C 6  alkyl or aralkyl; with the proviso that when R 1  represents ##STR4## and R 2  represents H then: (i) either R 3  and R 4  are other than H or --CH 3 , (ii) or R 7  is other than OR 12  and R 6  or R 8  is cycloalkyl having more than 7 carbon atoms, (iii) or R 7  is OR 12  but R 6  and R 8  are other than H, (iv) or R 7  is OR 12  but R 5  is other than H. 
     The bi-aromatic esters are employed in human and veterinary medicine and in cosmetic compositions.

The present invention relates to new bi-aromatic esters, to a processfor their preparation and to their use in human and veterinary medicinesand in cosmetic compositions.

These new bi-aromatic esters are also useful in the topical and systemictreatment of dermatologic ailments linked to a keratinization disorder(differentiation-proliferation) and dermatologic diseases, or others,having an inflammatory and/or immunoallergic component and indegeneration maladies of the conjunctive tissue. They also exhibit anantitumoral activity. Besides, these derivatives can be employed in thetreatment of atophy, be it cutaneous or respiratory, and in rheumatoidpsoriasis.

They are also useful in the ophthalmologic field, principally in thetreatment of corneopathies.

The bi-aromatic esters in accordance with the present invention can berepresented by the following formula ##STR5## wherein R₁ representshydrogen, OH, --CH₃, --CH₂ OH, --CH(OH)CH₃, ##STR6## R₉ representshydrogen, alkyl having 1-6 carbon atoms, monohydroxyalkyl orpolyhydroxyalkyl,

R₁₀ represents OH, alkyl having 1-6 carbon atoms or ##STR7## r' and r"represent hydrogen, alkyl having 1-6 carbon atoms, aryl, aralkyl,monohydroxyalkyl or polyhydroxyalkyl, or r' and r" together form aheterocycle,

R₂ represents hydrogen, alkyl having 1-6 carbon atoms, OR₉, fluorine or--CF₃,

R₃, R₄ and R₅ represent hydrogen, fluorine, OH, --CH₃, --OCH₃, --CF₃,--COOH or --CH₂ OH,

R₆ and R₈ represent hydrogen, --CF₃, α-substituted alkyl having 3-5carbon atoms, α,α'-disubstituted alkyl having 4-12 carbon atoms,cycloalkyl having 3-12 carbon atoms, mono- or polycyclic cycloalkylhaving 5-12 carbon atoms whose linking carbon is trisubstituted or--SR₁₁, --SO₂ R₁₁ or --SOR₁₁,

R₁₁ represents alkyl having 1-6 carbon atoms or cycloalkyl,

R₆ and R₈ cannot simultaneously represent hydrogen,

R₇ represents hydrogen, alkyl having 1-6 carbon atoms, alkenyl,alkenyloxy, OR₁₂, SR₁₃, SOR₁₄ or SO₂ R₁₄,

R₁₂ represents hydrogen, alkyl having 1-6 carbon atoms alkenyl, mono orpolyhydroxyalkyl or --(CH₂)_(n) --COR₁₅, n being 0.1 or 2 and R₁₅representing hydrogen, OH, alkyl having 1-6 carbon atoms or alkoxyhaving 1-6 carbon atoms,

R₁₃ represents hydrogen, alkyl having 1-6 carbon atoms or aralkyl,

R₁₄ represents OH, alkyl having 1-6 carbon atoms or aralkyl, with theproviso that when R₁ represents --CH₂ OH, --CH(OH)CH₃, ##STR8## and R₂represents hydrogen, then: either R₃ and R₄ are other than hydrogen or--CH₃,

(ii) or R₇ is other than OR₁₂ and R₆ or R₈ is cycloalkyl having morethan 7 carbon atoms,

(iii) or R₇ represents OR₁₂, but R₆ and R₈ are then other than hydrogen,

(iv) or R₇ represents OR₁₂ but then R₅ is other than

The compounds in accordance with the present invention can also beprovided in the form of salts when they have an acid function. It isthen a case of an alkali metal salt, an alkaline earth metal salt oreven zinc salts or organic amine salts.

By alkyl having 1-6 carbon atoms is meant, preferably, methyl, ethyl,isopropyl, butyl and tert.butyl.

By α-substituted alkyl having 3-15 carbon atom is meant isopropyl,1-methyl propyl, 1-ethyl propyl, 1-methyl hexyl, 1-methyl decyl or1-ethyl dodecyl.

By α,α'-disubstituted alkyl having 4-12 carbon atoms is meantprincipally tert.butyl, 1,1-dimethyl propyl, 1-methyl-1-ethyl propyl,1-methyl-1-ethyl hexyl or 1,1-dimethyl decyl.

By monohydroxyalkyl is meant a radical having 2 or 3 carbon atoms,principally 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl.

By polyhydroxyalkyl is meant a radical containing 3-6 carbon atoms and2-5 hydroxyl groups such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl,2,3,4,5-tetrahydroxypentyl or the residue of pentaerythritol.

By alkenyl is meant a radical having 2-6 carbon atoms such as vinyl,allyl or 2-butenyl.

By aryl is meant phenyl optionally substituted by at least one halogen,hydroxyl or nitro function.

By aralkyl is meant benzyl or phenethyl optionally substituted by atleast one halogen, hydroxyl or nitro function.

By cycloalkyl is meant cyclopentyl or cyclohexyl.

By mono or polycyclic cycloalkyl having 5-12 carbon atoms whose linkingcarbon is trisubstituted is meant 1-methyl cyclohexyl or 1-adamantyl.

When the r' and r" radicals taken together form a heterocycle, theheterocycle preferably is a piperidino, morpholino, pyrrolidino orpiperazino radical, optionally substituted in the 4 position by a C₁ -C₆alkyl or a mono- or polyhydroxyalkyl such as defined above.

Representative compounds of formula (I) above include principally thefollowing:

4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-3-fluorobenzoic acid,

4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-fluorobenzoic acid,

4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-methylbenzoic acid,

4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-hydroxybenzoic acid,

4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-methoxybenzoic acid,

4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-3-methoxybenzoic acid,

4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-trifluoromethylbenzoic acid,

methyl 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-hydroxybenzoate,

4-[5-(1-adamantyl)-2-fluoro-4-methoxybenzoyloxy]benzoic acid,

4-[5-(1-adamantyl)-2,4-dimethoxybenzoyloxy] benzoic acid,

4-[3-(1-adamantyl) benzoyloxy] benzoic acid,

4-(3,5-di.tert-butyl-4-hydroxybenzoyloxy) benzoic acid,

4-[3-(1-adamantyl)-4-vinylbenzoyloxy] benzoic acid,

4-[3-(1-adamantyl)-4-ethylbenzoyloxy] benzoic acid,

4-[3-(1-adamantyl)-4-butylbenzoyloxy] benzoic acid,

4-[3-(1-adamantyl)-4-allyloxybenzoyloxy] benzoic acid,

4-[3-(1-adamantyl)-4-methoxybenzoyloxy] isophthalic acid,

4-[3-(1-adamantyl)-4-methoxybenzoyloxy] benzenesulfonamide,

4-hydroxyphenyl 3-(1-adamantyl)-4-methoxybenzoate,

phenyl 3-(1-adamantyl)-4-methoxybenzoate,

4-methylphenyl 3-(1-adamantyl)-4-methoxybenzoate,

4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-3-hydroxymethyl benzoic acid,

4-[3-(1-adamantyl)-4-methylthiobenzoyloxy]-benzoic acid,

4-[3-(1-adamantyl)-4-acetoxybenzoyloxy] benzoic acid,

4-[3-(1-adamantyl)-4-methylsulfonebenzoyloxy] benzoic acid,

4-[3-(1-adamantyl)-4-(carboxy methyleneoxy) benzoyloxy] benzoic acid,

4-[3-(1-adamantyl)-4-(2,3-dihydroxypropyloxy) benzoyloxy] benzoic acid,and

4-[3-(1-adamantyl-4-methoxycarbonylmethyloxy] benzoic acid.

The particularly preferred compounds of the present invention can berepresented by the following formula ##STR9## wherein (i) either R₃ toR₉ have the same meanings defined above for formula (I) and

R₂ represents alkyl having 1-6 carbon atoms, OR₉, fluorine or --CF₃,

(ii) or R₂ to R₄ and R₆ to R₉ have the same meanings given above forformula (I) and R₅ represents fluorine.

The present invention also relates to a process for the preparation ofthe compounds of formula (I).

(a) When R₁ represents hydrogen or --CH₃, the compounds in accordancewith the present invention can be pr®pared in accordance with thefollowing reaction scheme: ##STR10## The principal step in this processresides in reacting in an anhydrous medium, in an organic solvent suchas tetrahydrofuran or methylene chloride containing a tertiary amine(pyridine or triethylamin), or an alkaline hydride, such as sodiumhydride, an activated form of a substituted benzoic acid, for example,an acid chloride (1), on a mixed anhydride, with a benzene compoundhaving a hydroxy function para to the R₁ radical (2), the reaction beingcarried out at ambient temperature and with stirring.

(b) For the other meanings of R₁, the compounds are prepared byprotecting R₁ by an allylic or benzylic type protective group.

The synthesis to the free form can be carried out, in the case of anallylic protective group, by means of a catalyst such as certaincomplexes of a transition metal in the presence of a secondary amine,and in the case of a benzylic protective group, by debenzylation in thepresence of hydrogen, by means of a catalyst such as palladium oncharcoal. When R₁ =OH the protective group preferably is benzylic. WhenR₁ =--CH₂ OH or CH(OH)CH₃, it preferably is allylic. When R₁ =COOR₉, itcan be either allylic or benzylic, when R₁ =COOH, the compounds offormula Ia can be prepared in accordance with the following reactionscheme: ##STR11##

The action of the acid chloride (1) with an allyl p-hydroxybenzoate (3),optionally mono- or polysubstituted, in the presence of a tertiary aminesuch as pyridine or triethylamine, leads to allylic esters (Ib). Thesynthesis route to the free acid can be carried out by means of acatalyst such as certain complexes of a transition metal such as tris(triphenylphosphine) rhodium (1) chloride or tetrakis(triphenylphosphine) palladium (O) in the presence of a secondary amine.

The acid (Ic) thus obtained can be converted in a known manner into thecorresponding acid chloride which, when treated by an alcohol, (R₉ OH),or an amine, ##STR12## gives the corresponding ester or amide.

The present invention also relates to, as a medicine, the compounds offormula (I) such as defined above.

The compounds in accordance with the present invention exhibit goodstability to light and oxygen.

These compounds exhibit good activity in the differentiation test ofmice embryonic teratocarcinoma cells (F9 cells) (Cancer Research 43, p.5268, 1983), and/or in the inhibition test of ornithine decarboxylaseafter induction by "tape stripping" nude rat (Lab. Animale 21, p.233-240, 1987) and/or in the ear edema test induced by topicalapplication of arachidonic acid on mice (J. Invest. Dermatol. 82, p.367-371, 1984 . These tests show the activities of the compoundsrespectively in the fields of differentiation, proliferation andinflammation.

Finally, the new compounds are characterized by the introduction, intothe chemical structure, of an ester linkage highly sensitive to theaction of various esterases in vivo. which lends to the rapidinactivation of the molecules by conversion into biologically inactivefragments.

The compounds in accordance with the present invention are indeedparticularly suitable in the following treatment fields:

(1) for the treatment of dermatologic ailments linked to akeratinization disorder causing differentiation and proliferation andprincipally for treating common acne, comedons, polymorphs, nodulokysticacne, conglobata, senile acne, secondary acne such as solar, medicinaland professional acne;

(2) for the treatment of other types of keratinization disorders,principally ichthyoses, ichthyosiform conditions, Darier malady,palmoplantary keratodermies, leucophasies and leucoplasiform conditionsand lichen;

(3) for the treatment of dermatologic ailments linked to akeratinization disorder having an inflammatory and/or immunoallergiccomponent and principally, all forms of psoriasis, be they cutaneous,mucous or ungual, and even psoriasic rheumatism, or again cutaneousatopies, such as eczema, or respiratory atopy; the compounds can also beused in certain inflammatory ailments not exhibiting any keratinizationdisorder;

(4) for the treatment of all dermic or epidermic proliferations that arebenign or malignant, that are either of viral origin such as commonwarts, plane warts and epidermodysplasie verruciform, the proliferationbeing able to be induced by ultraviolet radiations, principally in thecase of baso epithelioma and cellular spino;

(5) for the treatment of other dermatologic disorders such as blisterydermatoses and collagen maladies;

(6) for the treatment of ophthalmologic disorders, and principally forthe treatment of corneopathies;

(7) for combatting against ageing of the skin, be it photoinduced ornot; and

(8) to prevent or heal scars of epidermic and/or dermic atopies, inducedby local or systemic corticosteroids, or any other form of cutaneousatophy.

The present invention also relates to medicinal compositions containingat least one compound of formula (I), such as defined above, or one ofits salts.

The present invention thus relates to a new medicinal composition,intended principally for the treatment of the ailments mentioned above,comprising in a pharmaceutically acceptable support at least onecompound of formula (I) and/or one of its salts.

The compounds according to the present invention are generallyadministered to a human or animal host at a daily dosage of about 0.01mg/kg to 100 mg/kg of body weight.

As the vehicle or support for these compositions any conventionalvehicle can be employed, the active component being found either in thedissolved state, or in the dispersed state, in said vehicle.

The administration of the compounds of the present invention can beeffected enterally, parenterally, topically or ocularly.

When administered enterally, the medicines can be provided in the formof tablets, gelules, lozenges, syrups, suspensions, solutions, powders,granules, emulsions or nanoparticles.

When administered parenterally, the medicinal compositions can beprovided in the form of solutions, suspensions or nanoparticles forperfusion or injection.

When administered topically, the pharxaceutical compositions based onthe compounds in accordance with the present invention and intended forthe treatment of the skin and mucous membranes are provided in the formof ointments, creams, milks, salves, powders, impregnated tampons,solutions, gels, lotions, sprays or suspensions. They can also beprovided in the form of lipidic or polymeric microspheres or vesicles orpolymeric patches or hydrogels so as to permit controlled release.

These topically applied compositions can be provided in anhydrous formor in aqueous form, according to clinical indications.

When administered ocularly, the medicinal composition is principally inthe form of an eyewash.

These compositions contain at least one compound of formula (I) such asdefined above or one of its salts, in an amount ranging, preferably,from 0.0001 to 5 percent by weight relative to the total weight of thecomposition.

The compounds of formula (I), in accordance with the present invention,are also useful in the cosmetic field, and in particular in body andhair hygiene compositions and principally for the treatment of skinhaving acne tendencies, to improve hair growth, to combat hair loss, tocombat against an oily appearance of the skin or hair, for theprotection against the harmful effects of the sun or in the treatment ofphysiologically dry skin.

The present invention thus relates to a cosmetic composition containing,in a cosmetically acceptable vehicle, an effective amount of at leastone compound of formula I or one of its salts, this composition beingprovided principally in the form of a lotion, gel, soap or shampoo.

The concentration of the compound of formula I in these cosmeticcompositions is between 0.0001 and 0.1 percent by weight and preferablybetween 0.001 and 0.01 percent by weight, based on the total weight ofthe composition.

The medicinal and cosmetic compositions according to the presentinvention can contain inert or even pharmacodynamic or cosmeticallyactive additives and principally: hydrating agents such asthiamorpholinone and its derivatives or urea; antiseborrheic oranti-acne agents such as S-carboxymethylcysteine, S-benzycysteamine,their salts and their derivatives, tioxolane or benzoyl peroxide;antibiotics such as erythromycin and its esters, neomycin, tetracyclineor 4,5-polymethylene-3-isothiazolinones; agents promoting the growth ofhair, such as "Minoxidil" (2,4-diamino-6-piperidino-3-pyrimidine oxide)and its derivatives, Diazoxide(7-chloro-3-methyl-1,2,4-benzothiadiazino-1,1-dioxide) and Phenytoin(5,5-diphenyl-2,4-imidazolidine dione); steroidal and non-steroidalanti-inflammatory agents; carotenoids and, principally, β-carotene;anti-psoriasic agents such as anthralin and its derivatives and5,8,11,4-eicosatetraynoic and 5,8,11-eicosatriynoic acids, and theiresters and amides.

The compositions according to the present invention can also includeflavor improving agents, preservatives, stabilizers, humidity regulatingagents, pH regulating agents, osmotic pressure modifying agents,emulsifiers, UV-A and UV-B filters, and antioxidants such asα-tocopherol, butylhydroxyanisole or butylhydroxytoluene.

The following non-limiting examples illustrate the preparation of theactive compounds of formula I according to the present invention as wellas compositions containing these compounds.

EXAMPLES OF PREPARATION EXAMPLE 1 -4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-3-fluorobenzoic acid (a) allyl3-fluoro-4-hydroxybenzoate

Into a round bottom flask, there are introduced 5.35 g (35 mmoles) of3-fluoro-4-hydroxybenzoic acid and 50 ml of allyl alcohol. 1 5 ml ofconcentrated sulfuric acid are added and the mixture is heated to 100°C. for 12 hours. The reaction medium is evaporated to dryness and 200 mlof water are added. The reaction medium is neutralized with sodiumbicarbonate and extracted with dichloromethane. The organic phase isdecanted, washed with water, dried on magnesium sulfate and evaporated.The residue obtained is purified by chromatography on a silica column byeluting with an 80:20 mixture of dichloromethane and hexane. 3.7 g (55%yield) of the expected ester having a melting point of 42°-43° C. arerecovered.

(b) allyl 4-(1-adamantyl)-4-methoxy benzoyloxy]-3-fluorobenzoate

The 3-(1-adamantyl)-4-methoxybenzoyl chloride prepared starting with 2.8(10 mmoles) of 3-(1-adamantyl)-4-methoxy benzoic acid, described inExample 1(b) of European patent application No. 0.232.199 is dissolvedin 50 ml of tetrahydrofuran (THF). The solution is slowly added to amixture of 1.96 g (10 mmoles) of allyl 3-fluoro-4-hydroxybenzoate and1.5 ml (10 mmoles) of triethylamine in 50 ml of THF. The mixture isstirred for 12 hours at ambient temperature. The reaction medium is thenpoured into water, and extracted with ethyl ether. The organic phase isdecanted, washed with water, dried on magnesium sulfate and evaporated.The residue is purified by chromatography on a silica column by elutingwith a 50:50 mixture of dichloromethane and hexane. After evaporation ofthe solvents, 3.3 g (72% yield) of the expected ester having a meltingpoint of 123°-125° C. are obtained.

(c) 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-3-fluorobenzoic acid

Into a round bottom flask and under a nitrogen stream, there areintroduced 108 mg (3.6 mmoles) of sodium hydride (80% in oil) and 20 mlof THF). There are then slowly added 546 μl (3.6 mmoles) of ethylmalonate and the mixture is stirred at ambient temperature until thecessation of gaseous emission.

This solution is slowly introduced into a mixture of 1.65 g (3.6 mmoles)of the ester obtained in Example 1(b) above, 208 mg of tetrakis(triphenylphosphine palladium (O) and 30 ml of THF. The reaction mixtureis stirred for 1 hour at ambient temperature, and then evaporated. Theresulting residue is pulverized in 100 ml of ethyl ether and the sodiumsalt is filtered. The solid is introduced into 100 ml of water,acidified to pH 1 with concentrated HCl and extracted with ethyl ether.The organic phase is decanted, dried on magnesium sulfate andevaporated. 1.1 g (72% yield) of4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-3-fluorobenzoic acid having amelting point of 258°-260° C. are obtained.

EXAMPLE 2 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-fluorobenzoic acid(a) allyl 2-fluoro-4-hydroxybenzoate

In a manner analogous to Example 1(a), starting with 8.3 g 53 mmoles) of2-fluoro-4-hydroxybenzoic acid treated for 2 hours at 100° C. with 60 mlof allyl alcohol and 1.5 ml of concentrated sulfuric acid, 7.2 g (69%yield) of the expected ester having a melting point of 80°-81° C. areobtained.

(b) allyl 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-fluorobenzoate

To a mixture of 1.96 g (10 mmoles) of allyl 2-fluoro-4-hydroxybenzoate,1.53 ml (11 mmoles) of triethylamine and 25 ml of THF, there is slowlyadded a solution of 3 g (10 mmoles) of 3-(1-adamantyl)-4-methoxybenzoylchloride in 50 ml of THF. The reaction medium is stirred at ambienttemperature for 12 hours and then poured into water and extracted withethyl ether. The organic phase is decanted, washed with water, dried onmagnesium sulfate and evaporated. The resulting residue is purified bychromatography on a silica column, eluted by a 50:50 mixture ofdichloromethane and hexane. After evaporation of the solvents, 3.63 g(78% yield) of the expected ester having a melting point of 102°-104° C.

(c) 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-fluorobenzoic acid

Into a three neck flask and under a nitrogen current, there areintroduced 2.32 g (5 mmoles) of the ester obtained in 2(b), above, 145mg of tetrakis (triphenylphosphine) palladium (O) and 25 ml of anhydrousTHF. There are then slowly added 4.35 ml (50 mmoles of morpholine andthe mixture is stirred at ambient temperature for 1 hour. The reactionmedium is evaporated to dryness and the residue is pulverized in ethylether. The formed morpholine salt is filtered off and introduced into100 ml of water, acidified to pH 1 with concentrated HCl and extractedwith ethyl ether. The organic phase is decanted, washed with water,dried on magnesium sulfate and evaporated. The solid is pulverized in 20ml of ethyl ether, filtered and dried. 1.86 g (88% yield) of theexpected acid having a melting point of 254°-256° C. are obtained.

EXAMPLE 3 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-methylbenzoic acid(a) allyl 4-hydroxy-2-methylbenzoate

In a manner analogous to Example 1(a), 5.34 g (32 mmoles) of4-hydroxy-2-methyl benzoic acid treated at 100° C. for 12 hours with 50ml of allyl alcohol and 1.5 ml of concentrated sulfuric acid, give 4 g(76% yield) of the expected ester having a melting point of 76°-77° C.

(b) allyl 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-methylbenzoate

Into a three neck flask and under a nitrogen current, there areintroduced 330 mg (11 mmoles) of sodium hydride (80% in oil) and 20 mlof THF. There is then slowly added a solution of 1.92 g (10 mmoles) ofthe ester prepared in Example 3(a), above, and the mixture is stirred atambient temperature until the cessation of gaseous emission. There isthen slowly introduced a solution of 3 g (10 mmoles) of3-(1-adamantyl)-4-methoxybenzoyl chloride in 30 ml of THF and themixture is stirred at ambient temperature for six hours. The reactionmedium is poured into water and extracted with ethyl ether. The organicphase is decanted, washed with water, dried on magnesium sulfate andevaporated. The resulting residue is purified by chromatography on asilica column, eluted with a 40:60 mixture of dichloromethane andhexane. After evaporation of the solvents, 2.9 g (63% yield) of theexpected ester having a melting point of 136°-137° C. are recovered.

(c) 4-[3-(1-adamantyl)-4-methoxybenzoyloxy-2

methylbenzoic acid

In a manner analogous to Example 2(c), starting with 1.38 g (3 mmoles)of allyl 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-methylbenzoate, 780mg of 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-methylbenzoic acidhaving a melting point of 236°-237° C. are obtained.

EXAMPLE 4 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-hydroxybenzoic acid

(a) benzyl 2,4-dihydroxybenzoate

To a solution of 3 g (0.1 mole) of sodium hydride (80% in oil) and 50 mlof dimethylformamide (DMF), there are slowly added 15.4 g (0.1 mole) of2,4-dihydroxybenzoic acid dissolved in 50 ml of DMF. The mixture isstirred at ambient temperature until the cessation of gaseous emission.There are then added 13.1 ml (0.1 mole) of benzyl bromide and themixture is stirred at ambient temperature until solubilization of thereaction medium. The reaction mixture is poured into water, andextracted with ethyl ether. The organic phase is decanted, washed withwater, dried on magnesium sulfate and evaporated. The residue ispurified by chromatography on a silica column by eluting withdichloromethane. 19.7 g (81% yield) of the expected ester having amelting point of 94°-95° C. are recovered.

(b) benzyl 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-hydroxybenzoate

In a manner analogous to Example 2 b) starting with 9.8 g (40 mmoles) ofbenzyl 2,4-dihydroxybenzoate, 16.5 g (81% yield) of benzyl4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-hydroxybenzoate having amelting point of 171°-172° C. are obtained.

(c) 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-hydroxybenzoic acid

Into a reactor, there are introduced 5.1 g (10 mmoles) of the esterobtained in Example 4(b) above, 1 g of palladium on charcoal (5%) and250 ml of dioxan. Hydrogenation is carried out at ambient temperatureand under a pressure of 4 bars, for 1 hour. The catalyst is filtered andthe filtrate is evaporated. The resulting solid is pulverized in 100 mlof ethyl ether. After filtering and drying, 3.6 g (86% yield) of4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-hydroxy benzoic acid having amelting point of 243°-244° C. are obtained.

EXAMPLE 5 4-[3-adamantyl)-4-methoxybenzoyloxy]-2-methoxybenzoic acid (a)benzyl 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-methoxybenzoate

To a solution of 5.12 g (10 mmoles) of benzoyl4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-hydroxybenzoate and 200 ml ofDMF, there are added, in small portions, 360 mg (12 mmoles) of sodiumhydride (80% in oil). The mixture is stirred at ambient temperatureuntil the cessation of gaseous emission. 750 μl (12 mmoles) of methyliodide are added and the mixture is stirred for 4 hours at ambienttemperature. The reaction medium is poured into water and extracted with300 ml of ethyl ether. The organic phase is decanted, washed with water,dried on magnesium sulfate and evaporated. The resulting residue ispurified by chromatography on a silica column eluted withdichloromethane. After evaporation of the solvent, 4.9 g (94% yield) ofthe expected ester having a melting point of 102°-103° C. are recovered.

(b) 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-methoxybenzoic acid

Into a reactor, there are introduced 4.5 g (8.5 mmoles) of the benzylicester obtained in Example 5(a), above, 450 mg of palladium on charcoal(5%) and 120 ml of dioxan. Hydrogenation is effected at ambienttemperature and under a pressure of 4 bars for 2 hours. The catalyst isfiltered and the filtrate is evaporated. The resulting solid ispulverized in 50 ml of ethyl either, filtered and dried. 3 g (82% yield)of 4-[3-(1 -adamantyl)-4-methoxybenzoyloxy]-2-methoxybenzoic acid havinga melting point of 199°-200° C. are recovered.

EXAMPLE 6 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-3-methoxybenzoic acid(a) allyl 4-hydroxy-3-methoxybenzoate

In a manner analogous to Example 1(a), 5 g (30 mmoles) of 4-hydroxy-3-methoxybenzoic acid treated at 100° C. for 4 hours with 50 mlof allyl alcohol and 820 μl of concentrated sulfuric acid, give 4.65 g(75% yield) of the expected ester in the form of a slightly yellow oil.

(b) allyl 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-3-methoxybenzoate

In a manner analogous to Example 2(b) starting with 2.35 g (12 mmoles)of allyl 4-hydroxy-3-methoxy benzoate, 4.12 g (77% yield) of theexpected ester having a melting point of 146°-148° C. are obtained.

(c) 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-3-methoxybenzoic acid

In a manner analogous to Example 1 c), starting with 2 g (4.2 mmoles) ofthe ester prepared in Example 6(b), 1.35 g (74% yield) of4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-3-methoxybenzoic acid having amelting point of 282°-284° C. are obtained.

EXAMPLE 74-[3-(1-adamantyl)-4-methoxybenzoyloxy]2-trifluoromethylbenzoic acid (a)allyl 4-hydroxy-2-trifluoromethylbenzoate

In a manner analogous to Example 1(a) starting with 2 g (9.7 mmoles) of4-hydroxy-2-trifluoromethylbenzoic acid treated at 100° C. for 12 hourswith 20 ml of allyl alcohol and 260 μl of concentrated sulfuric acid,give 1.4 g (59% yield) of the expected ester having a melting point of82°-83°.

(b) allyl4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-trifluoromethylbenzoate

In a manner analogous to Example 2(b) 1.78 g (66% yield) of the expectedester having a melting point of 100°-102° C. are obtained.

(c) 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-trifluoromethylbenzoicacid

In a manner analogous to Example 1(c), starting with 1.78 g (3.46mmoles) of the allyl ester prepared in Example 7(b) above, 700 mg (39%yield) of the expected acid having a melting point of 228°-230° C. areobtained.

EXAMPLE 8 Methyl4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-hydroxybenzoate

Into a round bottom flask, there are introduced 1.68 g (10 mmoles) ofmethyl 2,4-dihydroxybenzoate, 1.55 ml (11 moles) of triethylamine and 50ml of THF. There is then slowly added a solution of 3 g (10 mmoles) of3-(1-adamantyl)-4-methoxybenzoyl chloride in 50 ml of THF and themixture is stirred at ambient temperature for 12 hours. The reactionmedium is poured into water and extracted with ethyl ether. The organicphase is decanted, washed with water, dried on magnesium sulfate andevaporated. The resulting residue is purified by chromatography on asilica column eluted by a 50:50 mixture of dichloromethane and hexane.After evaporation of the solvents, 2.55 g (59% yield) of methyl4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-hydroxybenzoate having amelting point of 125°-127° C. are recovered.

EXAMPLE 9 4-[5-(1-adamantyl)-2-fluoro-4-methoxy-benzoyloxy]benzoic acid(a) allyl 5-(1-adamantyl)-2-fluoro-4-hydroxy benzoate

To a solution of 3 g (20 mmoles) of 1-adamantanol in 10 ml of n-heptane,there are added, successively, 63 μl of concentrated sulfuric acid and2.16 ml (23 mmoles) of acetic anhydride. The mixture is stirred atambient temperature for 3 hours. There are then slowly added 540 μl (10mmoles) of concentrated sulfuric acid and then a solution of 3.92 g (20mmoles) of allyl 2-fluoro-4-hydroxybenzoate in 50 ml of dichloromethane.This mixture is stirred for 24 hours at ambient temperature. Thereaction medium is evaporated to dryness and the residue is introducedinto water and neutralized with sodium bicarbonate. The resulting solidis filtered and dried. The solid is purified by chromatography on asilica column by eluting with dichloromethane After evaporation of thesolvents, 3.86 g (58% yield) of the expected ester having a meltingpoint of 219°-222° C. are recovered.

(b) allyl 5-(1-adamantyl)-2-fluoro-4-methoxy benzoate

Into a three neck flask and under a nitrogen current, there areintroduced 350 mg (11.6 mmoles) of sodium hydride (80% in oil) and 10 mlof DMF. There is then slowly added a solution of 3.84 g (11.6 mmoles) ofthe ester prepared in Example 9(a), above, in 30 ml of DMF. The mixtureis stirred at ambient temperature until the cessation of gaseousemission. 730 μl 11.7 mmoles) of methyl iodide are slowly added and themixture is stirred at ambient temperature for 6 hours. The reactionmedium is poured into water and extracted with ethyl ether. The organicphase is decanted, washed with water, dried on magnesium sulfate andevaporated. The resulting residue is purified by chromatography on asilica column eluted with a 50:50 mixture of dichloromethane and hexane.After evaporation of the solvents, 2.9 g (72% yield) of allyl5-(1-adamantyl)-2-fluoro-4-methoxybenzoate having a melting point of101°-102° C. are recovered.

(c) 5-(1-adamantyl)-2-fluoro-4-methoxybenzoic acid

A suspension of 2.87 g (8.3 mmoles) of the ester obtained in Example9(b), above, in 100 ml of 2N methanolic soda is heated at reflux for 6hours. It is then evaporated to dryness and the residue is taken up inwater, acidified to pH 1 with concentrated HCl and extracted with ethylether. The organic phase is decanted, washed with water, dried onmagnesium sulfate and evaporated. 2.5 g (100% yield) of the expectedacid which melts at 282°-284° C. are obtained.

(d) 5-(1-adamantyl)-2-fluoro-4-methoxybenzoyl chloride

2.13 g (7 mmoles) of 5-(1-adamantyl)-2-fluoro-4-methoxybenzoic acid and20 ml of thionyl chloride are heated at reflux until the cessation ofgaseous emission. It is then evaporated to dryness and 2.26 g (100%yield) of the crude acid chloride, which is used as such for thefollowing synthesis, are obtained.

(e) allyl 4-[5-(1-adamantyl)-2-fluoro-4-methoxybenzoyloxy] benzoate

Into a round bottom flask there are introduced 1.25 g (7 mmoles) ofallyl 4-hydroxybenzoate, 1.1 ml (7 mmoles) of triethylamine and 20 ml ofTHF. There is slowly added a solution of 2.26 g (7 mmoles) of the acidchloride prepared in Example 9(d) in 60 ml of THF. The mixture isstirred at ambient temperature for 20 hours. The reaction medium ispoured into water, and extracted with ethyl ether. The organic phase isdecanted, washed with water, dried on magnesium sulfate and evaporated.The resulting residue is purified by chromatography on a silica columnby eluting with 70:30 mixture of dichloromethane and hexane. Afterevaporation of the solvents, 2.4 g (74% yield) of the expected esterhaving a melting point of 130°-131° C. are recovered.

(f) 4-[5-(1-adamantyl)-2-fluoro-4-methoxybenzoyloxy] benzoic acid

In a manner analogous to Example 1(c), starting with 2.33 g (5 mmoles)of allyl 4-[5-(1-adamantyl)-2-fluoro-4-methoxybenzoyloxy] benzoate, 1.69g (79% yield) of 4-[5-(1-adamantyl)-2-fluoro-4-methoxybenzoyloxy]benzoic acid having a melting point of 268°-270° C. are obtained.

EXAMPLE 10 4-[5-(1-adamantyl)-2,4-dimethoxybenzoyloxy] benzoic acid (a)methyl 5-(1-adamantyl)-2,4-dihydroxybenzoate

In a manner analogous to Example 9(a), starting with 24.5 g (0.146 mole)of methyl 2,4-dihydroxybenzoate, 32.5 g (74% yield) of methyl5-(1-adamantyl)-2,4-dihydroxybenzoate having a melting point of167°-169° C. are obtained.

(b) methyl 5-(1-adamantyl)-2,4-dimethoxybenzoate

To a suspension of 1.32 g (44 mmoles) of sodium hydride (80% in oil) in30 ml of DMF, there is slowly added a solution of 6 g (20 mmoles) of theester prepared in Example 10(a) above in 100 ml of DMF. The mixture isstirred at ambient temperature until the cessation of gaseous emission.There are then added 2.75 ml (44 mmoles) of methyl iodide and themixture is stirred at ambient temperature for 24 hours. The reactionmedium is poured into water and extracted with ethyl ether. The organicphase is decanted, washed with water, dried on magnesium sulfate andevaporated. The resulting residue is purified by chromatography on asilica column eluted with a 90:10 mixture of dichloromethane and hexane.After evaporation of the solvents, 3.4 g (51% yield) of the expectedester having a melting point of 148°-151° C. are recovered.

(c) 5-(1-adamantyl)-2,4-dimethoxybenzoic acid

In a manner analogous to Example 9(c), starting with 3.3 g (10 mmoles)of the methyl ester prepared in Example 10 (b) above, 3 g (94% yield) of5-(1-adamantyl)-2,4-dimethoxybenzoic acid having a melting point of213°-214° C. are obtained.

(d) 5-(1-adamantyl)-2,4-dimethoxybenzoyl chloride

In a manner analogous to Example 9(d), starting with 2.94 g (9.3 mmoles)of 5-(1-adamantyl)-2,4-dimethoxybenzoic acid, 3.12 g (100% yield) of thecrude acid chloride, which is used as such in the following synthesis,are obtained.

(e) allyl 4-[5-(1-adamantyl)-2,4-dimethoxybenzoyloxy] benzoate

In a manner analogous to Example 9(e), by the reaction of 3.12 g (9.3mmoles) of the acid chloride prepared in Example 10(d), above, with 1.66g (9.3 mmoles) of allyl 4-hydroxybenzoate, 1.8 g (41% yield) of theexpected ester having a melting point of 120°-121° C. are obtained.

(f) 4-[5-(1-adamantyl)-2,4-dimethoxybenzoyloxy] benzoic acid

In a manner analogous to Example 1(c), starting with 1.77 g (3.71mmoles) of the ester prepared in Example 10(e), above, 1.16 g (72%yield) of 4-[5-(1-adamantyl)-2,4-dimethoxy-benzoyloxy] benzoic acidhaving a melting point of 236°-238° C. are obtained.

EXAMPLE 11 4-[3-(1-adamantyl) benzoyloxy] benzoic acid (a) methyl3-(1-adamantyl)-4-hydroxybenzoate

In a manner analogous to Example 9(a), starting with 22.8 g (0.15 mole)of methyl 4-hydroxybenzoate, 36 g (84% yield) of methyl3-(1-adamantyl)-4-hydroxybenzoate having a melting point of 183°-184° C.are obtained.

(b) methyl 3-(1-adamantyl)-4-(trifluoromethyl) sulfonyloxy benzoate

A solution of 14.4 g (50.4 mmoles) of methyl3-(1-adamantyl)-4-hydroxybenzoate, 13.6 ml (168 mmoles) of pyridine, 61mg (0.5 mmoles) of 4-dimethylaminopyridine and 100 ml of anhydrousdichloromethane sulfonic anhydride is cooled to -78° C. There are slowlyadded 10 ml (59.5 mmoles) of trifluoromethane. The temperature ispermitted to rise to 20° C. and the mixture is stirred for 6 hours. Thereaction medium is poured into water, acidified to pH 1 withconcentrated HCl and extracted with dichloromethane. The organic phaseis decanted, washed with water, dried on magnesium sulfate andevaporated. The resulting residue is purified by chromatography on asilica column by eluting with hexane. After evaporation of the solvents,17.5 g (83% yield) of the expected product having a melting point of90°-91° C. are obtained.

(c) methyl 3-(1-adamantyl) benzoate

Into a round bottom flask, there are introduced 3 g (7 mmoles) of methyl3-(1-adamantyl)-4-(trifluoromethyl) sulfonyloxybenzoate, 415 mg (0.36mmoles) of tetrakis (triphenylphosphine) palladium (O), 3 ml (21.5mmoles) of triethylamine and 15 ml of DMF. There are then slowly added547 μl (14.4 mmoles) of formic acid and the mixture is heated at 80° C.for 1 hour. The reaction medium is poured into water and extracted withethyl ether. The organic phase decanted, washed with water, dried onmagnesium sulfate and evaporated. The resulting residue is purified bychromatography on a silica column eluted with hexane. 1.78 g (90% yield)of methyl 3-(1-adamantyl) benzoate having a melting point of 147°-149°C. are recovered.

(d) 3-(1-adamantyl) benzoic acid

In a manner analogous to Example 9(c), starting With 3.45 g (12.7mmoles) of the ester prepared in Example 11(c), 2.81 g (86% yield) of3-(1-adamantyl) benzoic acid having a melting point of 247°-249° C. areobtained.

(e) 3-(1-adamantyl) benzoyl chloride

In a manner analogous to Example 9(d) starting with 1.4 g (5.5 mmoles)of 3-(1-adamantyl) benzoic acid, 1.5 g (100% yield) of the crude acidchloride, which is used as such in the following synthesis, areobtained.

(f) allyl 4-[3-(1-adamantyl) benzoyloxy] benzoate

In a manner analogous to Example 9(a) by reacting 1.5 g (5.5 mmoles) of3-(1-adamantyl) benzoyl chloride with 980 mg (5.5 mmoles) of allyl4-hydroxybenzoate, 1.5 g (68% yield) of the expected ester in the formof a colorless oil are obtained.

(g) 4-[3-(1-adamantyl) benzoyloxy] benzoic acid

In a manner analogous to Example 1(c), starting With 1.45 g (3.6 mmoles)of allyl 4-[3-(1-adamantyl) benzoyloxy] benzoate, 600 mg (40% yield) of4-[3-(1-adamantyl) benzoyloxy] benzoic acid having a melting point of237°-239° C. are obtained.

EXAMPLE 12 4-[3,5-di-tert.butyl-4-hydroxybenzoyloxy] benzoic acid (a)3,5-di-tert.butyl-4-hydroxybenzoyl chloride

1.88 g (7.5 mmoles) of 3,5-di-tert.butyl-4-hydroxybenzoic acid and 15 mlof thionyl chloride are heated at reflux until the cessation of gaseousemission. It is then evaporated to dryness and 2.1 g (100% yield) of thecrude acid chloride, which is used as such in the following synthesis,are obtained.

(b) allyl 4-(3,5-di-tert.butyl-4-hydroxybenzoyloxy] benzoate

In a manner analogous to Example 9(c), starting with 2.1 g (7.5 mmoles)of the acid chloride prepared in Example 12(a) above with 1 g (7.5mmoles) of allyl 4-hydroxybenzoate, 1.48 g (49% yield) of the expectedester having a melting point of 114°-116° C are obtained.

(c) 4-[3,5-di-tert.butyl-4-hydroxybenzoyloxy] benzoic acid

In a manner analogous to Example 2(c), starting with 1.47 g (3.6 mmoles)of the ester prepared in Example 12(b), 750 mg (57% yield) of4-(3,5-di-tert.butyl-4-hydroxybenzoyloxy] benzoic acid which melts at223°-224° C. are obtained.

EXAMPLE 13 4-[3-(1-adamantyl)-4-vinylbenzoyloxy] benzoic acid

In a round bottom flask under argon, there are introduced 4.1 g (10mmoles) of methyl 3-(1-adamantyl)-4-(trifluoromethyl)sulfonyloxybenzoate in 50 ml of DMF. There are then added, successively,3.1 ml of vinyltributyltin (10.3 mmoles), 1.3 g (30 mmoles) of lithiumchloride and 141 mg (0.2 mmoles) of bis-(triphenylphosphine) palladium(II) chloride. The mixture is heated at 80° C. for 16 hours. Thereaction medium is poured into water, and extracted with ethyl ether.The organic phase is decanted, dried on magnesium sulfate andevaporated. The resulting residue is purified by chromatography on asilica column eluted by a 20:80 mixture of dichloromethane and hexane.2.7 g (93% yield) of the expected product having a melting point of86°-87° C. are recovered.

(b) 3-(1-adamantyl)-4-vinylbenzoic acid

Into a round bottom flask there are introduced 1.48 g (5 mmoles) of thepreceding ester, 100 ml of 2N methanolic soda and 250 ml of THF. Themixture is stirred at ambient temperature for 3 hours, and thenevaporated to dryness. The resulting residue is taken up in water andacidified to pH 1 with concentrated HCl. The resulting solid is filteredand dried under a vacuum in the presence of phosphorus pentoxide. 1.4 g(100% yield) of the expected product having a melting point of 315°-317°C. are recovered.

(c) 3-(1-adamantyl)-4-vinylbenzoyl chloride

Into a round bottom flask, there are introduced 1.4 g (5 mmoles) of3-(1-adamantyl)-4-vinylbenzoic acid in 100 ml of dichloromethane. Thereare slowly added 940 μl (5 mmoles) of dicyclohexylamine. After obtaininga homogenous reaction medium, there are slowly added 360 μl (5 mmoles)of thionyl chloride and the mixture is stirred at ambient temperaturefor 1 hour. It is then evaporated to dryness and the residue is taken upin 200 ml of ethyl ether. The dicyclohexylamine salt is filtered and thefiltrate is evaporated. 1.5 g (100% yield) of the crude acid chloride,which is used as such for the following synthesis, are obtained.

(d) allyl 4-[3-(1-adamantyl)-4-vinylbenzoyloxy] benzoate

In a manner analogous to Example 9(e) by reacting 1.35 g (4.5 mmoles) of3-(1-adamantyl)-4-vinylbenzoyl chloride with 800 mg (4.5 mmoles) ofallyl 4-hydroxybenzoate, 1.4 g (70% yield) of the expected ester in theform of a colorless oil are obtained.

(e) 4-[3-(1-adamantyl)-4-vinylbenzoyloxy] benzoic acid

In a manner analogous to Example 2(c), starting with 1.2 g (2.7 mmoles)of allyl 4-[3-(1-adamantyl)-4-vinylbenzoyloxy] benzoate, 750 mg (75%yield) of 4-[3-(1-adamantyl)-4-vinylbenzoyloxy]benzoic acid having amelting point of 235°-236° C. are obtained.

EXAMPLE 14 4-[3-(1-adamantyl)-4-ethylbenzoyloxy] benzoic acid (a) methyl3-(1-adamantyl)-4-ethylbenzoate

Into a reactor there are introduced 3 g (10 mmoles) of methyl3-(1-adamantyl)-4-vinylbenzoate, 270 mg of palladium on charcoal (5%)and 50 ml of dioxan. Hydrogenation is effected at ambient temperatureand under a pressure of 4 bars for 4 hours. The catalyst is filtered andthe filtrate is evaporated. 3 g (100% yield) of the expected product inthe form of a colorless oil are recovered.

(b) 3-(1-adamantyl)-4-ethylbenzoic acid

In a manner analogous to Example 13(b) starting with 2.54 g (8.5 mmoles)of the preceding ester. 2.4 g (100% yield) of3-(1-adamantyl)-4-ethylbenzoic acid are obtained.

(c) 3-(1-adamantyl)-4-ethylbenzoyl chloride

In a manner analogous to Example 9(d), starting with 2.3 g (8.1 mmoles)of the preceding acid, 2.35 g (100% yield) of the crude acid chloride,which is used as such in the following synthesis, are obtained.

(d) allyl 4-[3-(1-adamantyl)-4-ethylbenzoyloxy] benzoate

In a manner analogous to Example 9(e), by reacting 2.35 g (8.1 mmoles)of 3-(1-adamantyl)-4-ethylbenzoyl chloride with 1.44 g (8.1 mmoles) ofallyl 4-hydroxybenzoate, 2.54 g (71% yield) of the expected ester havinga melting point of 111°-113° C. are obtained.

(e) 4-[3-(1-adamantyl)-4-ethylbenzoyloxy] benzoic acid

In a manner analogous to Example 2(c), starting with 2.5 g (5.6 mmoles)of the ester prepared in Example 14(d), above, 1.65 g (73% yield) of4-[3-(1-adamantyl)-4-ethylbenzoyloxy] benzoic acid having a meltingpoint of 239°-241° C. are obtained.

EXAMPLE 15 4-[3-(1-adamantyl)-4-butylbenzoyloxy] benzoic acid

Into a round bottom flask and under argon, there are introduced 4.1 g(10 mmoles) of methyl 3-(1-adamantyl)-4-(trifluoromethyl)sulfonyloxybenzoate in 50 ml of DMF. There are then added, successively,3.6 ml (11 mmoles) of tetrabutyltin, 1.3 g 30 mmoles) of lithiumchloride and 141 mg (0.2 mmole) of bis-(triphenylphosphine) palladium(II) chloride. The mixture is heated at 80° C. for 24 hours. Thereaction medium is poured into water and extracted with ethyl ether. Theorganic phase is decanted, dried on magnesium sulfate and evaporated.The resulting residue is purified by chromatography on a silica columnby eluting with a 30:70 mixture of dichloromethane and hexane. Afterevaporation of the solvents, 2.6 g (80% yield) of the expected productin the form of slightly yellow oil are obtained.

(b) 3-(1-adamantyl)-4-butylbenzoic acid

In a manner analogous to Example 13 b), starting with 2.3 g (7 mmoles)of the preceding ester, 2.1 g (100% yield) of 3-(1-adamantyl)-4-butylbenzoic acid having a melting point of 209°-210° C.are obtained.

(c) 3-(1-adamantyl)-4-butylbenzoyl chloride.

In a manner analogous to Example 9(d) starting with 2 g (6.4 mmoles) ofthe preceding acid, 2.1 g (100% yield) of the crude acid chloride, whichis used as such in the following synthesis, are obtained.

(d) benzyl 4-[3-(1-adamantyl)-4-butylbenzoyloxy] benzoate

The preceding acid chloride, dissolved in 50 ml of THF is added to amixture of 1.46 g (6.4 mmoles) of benzyl 4-hydroxybenzoate and 1 ml (7.1mmoles) of triethylamine in 50 ml of THF. The mixture is stirred atambient temperature for 8 hours. The reaction medium is poured intowater and extracted with ethyl ether. The organic phase is decanted,dried on magnesium sulfate and evaporated. The resulting residue ispurified by chromatography on a silica column by eluting with a 50:50mixture of dichloromethane and hexane. After evaporation of thesolvents, 2.2 g (75% yield) of the expected ester in the form of acolorless oil are recovered.

(e) 4-[3-(1-adamantyl)-4-butylbenzoyloxy] benzoic acid

Into a reactor, there are introduced 2 g (3.8 mmoles) of the esterprepared in Examples 15(d), 340 mg of palladium on charcoal (5%) and 100ml of dioxan. Hydrogenation is effected at ambient temperature and undera pressure of 4 bars for 4 hours. The catalyst is filtered and thefiltrate is evaporated. The resulting residue is purified bychromatography on a silica column eluted by a 70:30 mixture ofdichloromethane and ethyl ether. After evaporation of the solvents, 1.1g (68% yield) of 4-[3-(1-adamantyl)-4-butylbenzoyloxy] benzoic acidhaving a melting point of 205°-206° C. are recovered.

EXAMPLE 16 4-[3-(1-adamantyl)-4-allyloxybenzoyloxy] benzoic acid

To a solution of 1.17 g (3 mmoles) of4-[3-(1-adamantyl)-4-hydroxybenzoyloxy] benzoic acid in 100 ml of a50:50 mixture of THF and DMF, there are added, by small portions, 180 mg(6 mmoles) of sodium hydride (80% in oil). The mixture is stirred atambient temperature until the cessation of gaseous emission. There arethen added 260 μl (3 mmoles) of allyl bromide and the mixture is stirredat ambient temperature for 3 hours. The reaction medium is poured intowater, acidified to pH 4 with 1N HCl and extracted with ethyl ether. Theorganic phase, is decanted, washed with water, dried on magnesiumsulfate and evaporated. The resulting residue is purified bychromatography on silica eluted with ethyl ether. After evaporation ofthe solvent, 880 mg (68% yield) of4-[3-(1-adamantyl)-4-allyloxybenzoyloxy] benzoic acid having a meltingpoint of 260°-261° C. are recovered.

EXAMPLE 17 4-[3-(1-adamantyl)-4-methoxybenzoyloxy] isophthalic acid (a)benzyl 4-hydroxyisophthalate

To a solution of 5.5 g (30 mmoles) of 4-hydroxyisophthalic acid in 200ml of DMF, there are added, by small portions 1.8 g (60mmoles) of sodiumhydride (80% in oil). The mixture is stirred until the cessation ofgaseous emission. There are then added 7.2 ml (60 mmoles) of benzylbromide and the mixture is stirred for 4 hours at ambient temperature.The reaction medium is poured into water and extracted with ethyl ether.The organic phase is decanted, washed with water, dried on magnesiumsulfate and evaporated. The resulting residue is purified bychromatography on a silica column by eluting with a 30:70 mixture ofdichloromethane and hexane. After evaporation of the solvents, 6.5 g(60% yield) of the expected ester having a melting point of 68°-70° C.are recovered.

(b) benzyl 4-[3-(1-adamantyl)-4-methoxybenzoyloxy] isophthalate

In a manner analogous to Example 1(b), by reacting 5.4 g (18 mmoles) of3-(1-adamantyl)-4-methoxybenzyl chloride with 6.5 g (18 mmoles) ofbenzyl 4-hydroxyisophthalate, 7.5 g (67% yield) of benzyl4-[3-(1-adamantyl)-4-methoxybenzoyloxy] isophthalate having a meltingpoint of 102°-104° C. are obtained.

(c) 4-[3-(1-adamantyl)-4-methoxybenzoyloxy] isophthalic acid

In a manner analogous to Example 15(e), starting with 3.1 g (5 mmoles)of the preceding ester, 1.2 g (55% yield) of 4-[3-(1-adamantyl)-4-methoxybenzoyloxy] isophthalic acid having a melting pointof 172°-173° C. are obtained.

EXAMPLE 18 4-[3-(1-adamantyl)-4-methoxybenzoyloxy] benzenesulfonamide

Into a round bottom flask, there are introduced 2.86 g (10 mmoles) of3-(1-adamantyl)-4-methoxybenzoic acid, 1.73 g (10 mmoles) of4-hydroxybenzenesulfonamide and 50 ml of THF. There are added,successively, 2.1 g (10 mmoles) of 1,3-dicyclohexylcarbodiimide and then1.22 (10 mmoles) of 4-dimethylaminopyridine. The medium is stirred atambient temperature for 4 hours. The reaction medium is poured intowater and extracted with ethyl ether. The organic phase is decanted,washed with water, dried on magnesium sulfate and evaporated. Theresulting solid is purified by chromatography on a silica column elutedby a 60:40 mixture of ethyl ether and hexane. After evaporation of thesolvents, 2 g (46% yield) of 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]benzenesulfonamide having a melting point of 223°-224° C. are recovered.

EXAMPLE 19 4-hydroxyphenyl 3-(1-adamantyl)-4-methoxybenzoate (a)4-benzyloxyphenyl 3-(1-adamantyl)-4-methoxybenzoate

Into a three neck flask, under a nitrogen current, containing 663 mg (22mmoles) of sodium hydride (80% in oil), there are slowly added 4 g (20mmoles) of 4-benzoyloxyphenol in 30 ml of anhydrous THF. The mixture isstirred until the cessation of gaseous emission. There are then slowlyintroduced 6.4 g (20 mmoles) of 3-(1-adamantyl)-4-methoxybenzoylchloride in 60 ml of THF and the mixture is stirred at ambienttemperature for 4 hours. The reaction medium is poured into water,extracted with dichloromethane, washed with water, dried on magnesiumsulfate and evaporated. The resulting residue is pulverized in hexaneyielding 9 g (96% yield) of the expected ester having a melting point of183°-185° C.

(b) 4-hydroxyphenyl 3-(1-adamantyl)-4-methoxybenzoate

Into a reactor, there are introduced 4 g 8.5 mmoles) of the benzyl etherobtained in Example 19(a), 400 mg of palladium on charcoal (10%), 70 mlof dioxan, 70 ml of acetic acid and 0.2 ml of 12N HCl. The mixture isstirred at 50° C. under a pressure of 4 bars. After filtration andevaporation, the solid is taken up with 400 ml of dichloromethane andthe organic phase is washed with water. After drying on magnesiumsulfate, filtration and evaporation, 2.85 g (88% yield) of the expectedproduct having a melting point of 236°-237° C. are isolated.

EXAMPLE 20 Phenyl 3-(1-adamantyl)-4-methoxybenzoate

In a manner analogous to Example 3(b), 0.95 g (10 mmoles) of phenol in10 ml of THF are treated with 332 mg 11 moles) of sodium hydride (80% inoil). There is then slowly introduced a solution of 3.2 g (10 mmoles) of3-(1-adamantyl)-4-methoxybenzoyl chloride in 30 ml of THF. The reactionis permitted to proceed at ambient temperature for 4 hours. The reactionmedium is poured into water, extracted with ethyl ether, washed withwater, dried on magnesium sulfate and evaporated. The residue ischromatographed on silica, eluting with a 60:40 mixture of hexane anddichloromethane. After evaporation and precipitation in hexane, 3 g (83%yield) of the expected ester having a melting point of 165°-166° C. areisolated.

EXAMPLE 21 4-methylphenyl 3-(1-adamantyl)-4-methoxybenzoate

In a manner analogous to Example 3(b), 1.08 g (10 mmoles) of paracresolin 10 ml of THF are treated With 332 mg (11 mmoles) of sodium hydride(80% in oil). There is then slowly introduced a solution of 3.2 g (10mmoles) of 3-(1-adamantyl)-4-methoxybenzoyl chloride in 30 ml of THF.The reaction is permitted to proceed at ambient temperature overnight.The reaction medium is poured into water, extracted with ethyl acetate,washed with water, dried on magnesium sulfate and evaporated. Theresulting residue is recrystallized in ethyl acetate yielding 2.91 g(77% yield) of 4-methylphenyl 3-(1-adamantyl)-4-methoxybenzoate having amelting point of 206° C.

EXAMPLE 224-[3-(1-adamantyl)-4-methoxybenzoyloxy]-3-hydroxymethylbenzoic acid (a)benzyl 4-hydroxy-3-hydroxymethylbenzoate

A solution of 27.4 g (0.12 mole) of benzyl 4-hydroxybenzoate, 14.7 g(0.12 mole) of benzeneboronic acid, 6 g (0.135 mole) of paraformaldehydeand 0.9 ml (12 mmoles) of propionic acid in 600 ml of anhydrous benzeneis heated at reflux for 12 hours using a Dean-Stark reactor to separatethe water formed. The reaction medium is poured into bicarbonated Waterand extracted with ethyl ether. The organic phase is decanted, washedwith water, dried on magnesium sulfate and evaporated. The resultingresidue is purified by chromatography on a silica column eluted withdichloromethane. After evaporation of the solvent, 8.9 g (30% yield) ofthe expected product having a melting point of 109°-110° C. areobtained.

(b) benzyl 3-tert.butyldimethylsilyloxymethyl-4-hydroxybenzoate

To a solution of 2.7 g (10.5 mmoles) of benzyl4-hydroxy-3-hydroxymethylbenzoate in 50 ml of DMF, there are added,successively, 1.47 ml (10.5 mmoles) of triethylamine and 51 mg (0.4mmole) of 4-N,N-dimethylamino pyridine. The reaction medium is cooled to0° C. and there is slowly added a solution of 1.6 g (10.5 mmoles) oftert.butyldimethylsilyl chloride in 20 ml of DMF. The mixture is stirredat ambient temperature for 8 hours. The reaction medium is poured intowater and extracted with ethyl ether. The organic phase is decanted,dried on magnesium sulfate and evaporated. The resulting residue, whichcontains two products, is purified by chromatography on a silica column,by eluting with a 90:10 mixture of hexane and ethyl ether. 850 mg (23%yield) of benzyl 3-tert.butyldimethylsilyloxymethyl-4-hydroxybenzoate inthe form of colorless oil and 930 mg (27% yield) of benzyl4-tert.butyldimethylsilyloxy-3-hydroxymethylbenzoate in the form of aslightly yellow oil are obtained.

(c) benzyl4-[8-(1-adamantyl)-4-methoxybenzoyloxy]-3-tert.butyldimethylsilyloxymethylbenzoate

In a manner analogous to Example 1(b), by reacting 2.2 g (7.25 mmoles)of 3-(1)-adamantyl)-4-methoxybenzoyl chloride with 2.7 g (7.25 mmoles)of benzyl 3-tert.butyldimethylsilyloxymethyl-4-hydroxybenzoate, 3.1 g(71% yield) of the expected product in the form of colorless oil areobtained.

(d) benzyl4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-3-hydroxymethylbenzoate

To a solution of 2.7 g (4.5 mmoles) of the ester obtained in Example22(c) in 50 ml of THF, there are slowly added 5 ml of a molar solutionof tetrabutylammonium fluoride in THF. The mixture is stirred for 30minutes at ambient temperature. The reaction medium is poured into waterand extracted with ethyl ether. The organic phase is decanted, dried onmagnesium sulfate and evaporated. The resulting residue is purified bychromatography on a silica column eluted with dichloromethane. Afterevaporation of the solvent, 700 mg (30% yield) of the expected ester inthe form of an opaque oil are obtained.

(e) 4-[3-(1-adamantyl)-4-methoxybenzoyloxy[-3-hydroxymethylbenzoic acid

In a manner analogous to Example 15(e), starting with 700 mg (1.3mmoles) of the preceding ester, 300 mg (55% yield) of4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-3-hydroxymethyl benzoic acidhaving a melting point of 214°-216° C. are obtained.

EXAMPLE 23 4-[3-(1-adamantyl)-4-methylthiobenzoyloxy] benzoic acid (amethyl 3-(1-adamantyl)-4-(dimethylaminothiocarbonyloxy) benzoate

Into a round bottom flask, there are introduced 2.4 g (0.08 mole) ofsodium hydride (80% in oil) and 250 ml of DMF. Under a nitrogen current,there are slowly added 22.9 g (0.08 g mole) of methyl3-(1-adamantyl)-4-hydroxybenzoate. The mixture is stirred until thecessation of gaseous emission. There are then added, all at once, 12.9 g(0.104 mole) of dimethylthiocarbamoyl chloride and the mixture isstirred for 16 hours at ambient temperature. The reaction medium ispoured into water and extracted with ethyl ether. The organic phase isdecanted, dried on magnesium sulfate and evaporated. The resultingresidue is purified by chromatography on a silica column eluted with a70:30 mixture of dichloromethane and hexane. After evaporation of thesolvents, 1.8 g (63% yield) of the expected product having a meltingpoint of 174°-175° C. are recovered.

(b) methyl 3-(1-adamantyl)-4-(dimethylaminocarbonylthio) benzoate

17.9 g (0.048 mole) of the preceding ester are heated under a nitrogencurrent at 300° C. for 15 minutes. The resulting residue is purified bychromatography on a silica column eluted with a 90:10 mixture ofdichloromethane and hexane. After evaporation of the solvents, 14.2 g(80% yield) of the expected ester having a melting point of 150°-151° C.are recovered.

(c) 3-(1-adamantyl)-4-mercaptobenzoic acid

Into a round bottom flask there are introduced 14.2 g (38 mmoles) of thepreceding ester and 200 ml of 2N methanolic soda. The mixture is heatedat reflux for 4 hours. The reaction medium is evaporated to dryness. Theresidue is taken up in water, acidified to pH 1 with concentrated HCl,and extracted with ethyl ether. The organic phase is decanted, dried onmagnesium sulfate and evaporated. 10.9 g of the crude acid, which willbe used as such in the following synthesis, are recovered.

(d) methyl 3-(1-adamantyl)-4-methylthiobenzoate

Into a round bottom flask there are introduced 2.2 g (73 mmoles) ofsodium hydride (80% in oil) and 50 ml of DMF. There is then slowly addeda solution of 10.5 g (36.5 mmoles) of 3-(1-adamantyl)-4-mercaptobenzoicacid in 100 ml of DMF. The mixture is stirred until the cessation ofgaseous emission. There are then added 5.7 ml (92 mmoles) of iodomethaneand the mixture is stirred for 8 hours. The reaction medium is pouredinto water and extracted with ethyl ether. The organic phase isdecanted, dried on magnesium sulfate and evaporated. The resultingresidue is purified by chromatography on a silica column by eluting witha 40:60 mixture of dichloromethane and hexane. After evaporation of thesolvents, 10 g (87% yield) of the expected ester having a melting pointof 112°-113° C. are obtained.

(e) 3-(1-adamantyl)-4-methylthiobenzoic acid

In a manner analogous to Example 1(c), starting with 2 g (6.3 mmoles) ofthe preceding ester, 1.76 g (91% yield) of the expected acid having amelting point of 264°-265° C. are obtained.

(f) 3-(1-adamantyl)-4-methylthiobenzoyl chloride

1.7 g (5.6 mmoles) of 3-(1-adamantyl)-4-methylthiobenzoic acid and 20 mlof thionylchloride are heated at reflux until the cessation of gaseousemission. It is then evaporated to dryness and 1.8 g (100% yield) of thecrude acid chloride, which is used as such for the following synthesis,are obtained.

(g) tert.butyl 4-[3-(1-adamantyl)-4-methylthiobenzoyloxy] benzoate

Into a round bottom flask, there are introduced 1 g (5.6 mmoles) oftert.butyl 4-hydroxybenzoate, 780 μl (5.6 mmoles) of triethylamine and50 ml of THF. There are slowly added 1.8 g (5.6 mmoles) of the acidchloride prepared in Example 23(f) in 50 ml of THF. The mixture isstirred at ambient temperature for 8 hours. The reaction medium ispoured into water and extracted with ethyl ether. The organic phase isdecanted, dried on magnesium sulfate and evaporated. The resultingresidue is purified by chromatography on a silica column eluted with a60:40 mixture of dichloromethane and hexane. After evaporation of thesolvents, 2.1 g (76% yield) of the expected ester having a melting pointof 133°-134° C. are obtained.

(h) 4-[3-(1-adamantyl)-4-methylthiobenzoyloxy] benzoic acid

Into a round bottom flask, there are introduced 1.9 g (3.8 mmoles) ofthe preceding ester and 40 ml of carbon tetrachloride.

Under nitrogen there are slowly added 550 μl (3.8 mmoles) ofiodotrimethylsilane and the mixture is stirred at ambient temperaturefor 3 hours. The reaction medium is poured into water and extracted withethyl ether. The organic phase is decanted, dried on magnesium sulfateand evaporated. The resulting solid is recrystallized in ethyl acetate.After filtration and drying, 920 mg (57% yield) of4-[3-(1-adamantyl)-4-methylthiobenzoyloxy] benzoic acid having a meltingpoint of 276°-277° C. are obtained.

EXAMPLE 24 4-[3-(1-adamantyl)-4-acetoxybenzoyloxy] benzoic acid (a)benzyl 4-[3-(1-adamantyl)-4-acetoxybenzoyloxy benzoate

Into a round bottom flask there are introduced 66 mg (2.2 mmoles) ofsodium hydride (80% in oil) and 5 ml of THF. There is slowly added asolution of 964 mg (2 mmoles) of benzyl4-[3-(1-adamantyl)-4-hydroxybenzoyloxy] benzoate in 20 ml of THF. Themixture is stirred until the cessation of gaseous emission. There arethen introduced 150 μl (2.2 mmoles) of acetyl chloride and the mixtureis stirred at ambient temperature for 8 hours. The reaction medium ispoured into water, and extracted with ethyl ether. The organic phase isdecanted, dried on magnesium sulfate and evaporated. The resultingresidue is purified by simple filtration on silica by eluting withdichloromethane. After evaporation of the solvent, 870 mg (83% yield) ofthe expected product having a melting point of 131°-132° C. arerecovered.

(b) 4-[3-(1-adamantyl)-4-acetoxybenzoyloxy] benzoic acid

Into a reactor there are introduced 750 mg (1.4 mmoles) of the precedingester, 100 mg of palladium on charcoal (10%) and 20 ml of dioxan.Hydrogenation is effected at ambient temperature and under a pressure of6 bars for 2 hours. The catalyst is filtered and the filtrate isevaporated. The resulting residue is pulverized in the minimum of ethylether, filtered and dried. 500 mg (81% yield) of4-[3-(1-adamantyl)-4-acetoxybenzoyloxy] benzoic acid having a meltingpoint of 264°-265° C. are obtained.

EXAMPLE 25 4-[3-(1-adamantyl)-4-methylsulfoneloxy] benzoic acid (a)tert.butyl 4-[3-(1-adamantyl)-4-methylsulfonebenzoyloxy] benzoate

Into a round bottom flask there are introduced 940 mg (1.9 mmoles) oftert.butyl 4-[3-(1-adamantyl)-4-methylthiobenzoyloxy]benzoate and 40 mlof dichloromethane. There are then added at 0° C., 700 mg (4 mmoles) of3-chloroperoxybenzoic acid and the mixture is stirred at ambienttemperature for 6 hours. The reaction medium is poured into water andextracted with ethyl ether. The organic phase is decanted, dried onmagnesium sulfate and evaporated. The resulting residue is purified bychromatography on a silica column, eluted with ethyl ether. Afterevaporation of the solvent, 670 mg (67% yield) of the sulfone in theform of a slightly yellow oil are recovered.

(b) 4-[3-(1-adamantyl)-4-methylsulfonebenzoyloxy] benzoic acid

In a manner analogous to Example 23(h) starting with 630 mg (1.2 mmoles)of the preceding ester, 190 mg (35% yield) of4-[3-(1-adamantyl)-4-methylsulfonebenzoyloxy] benzoic acid having amelting point of 248°-250° C. are obtained.

EXAMPLE 26 4-[3-(1-adamantyl)-4-(carboxymethyleneoxy) benzoyloxy]benzoic acid (a) benzyl4-[3-(1-adamantyl)-4-(benzyloxycarbonylmethyleneoxy) benzoyloxy]benzoate

In a manner analogous to Example 24(a) by reacting 964 mg (2 mmoles) ofbenzyl 4-[3-(1-adamantyl)-4-hydroxybenzoyloxy] benzoate with 350 μl (2.2mmoles) of benzyl 2-bromo acetate, 800 mg (63% yield) of the expectedproduct having a melting point of 129°-130° C. are obtained.

(b) 4-3-(1-adamantyl)-4-(carboxymethyleneoxy) benzoyloxy] benzoic acid

In a manner analogous to Example 21(b) starting with 750 mg (1.2 mmoles)of the preceding ester, 400 mg (75% yield) of the expected acid having amelting point of 287°-288° C. are obtained.

EXAMPLE 27 4-[3-(1-adamantyl)-4-(2,3-dihydroxypropyloxy) benzoyloxy]benzoic acid (a) methyl3-(1-adamantyl)-4-(2,2-dimethyl-1,3-dioxolane-4-methyloxy) benzoate

Into a three neck flask containing 10.0 g (34.9 mmoles) of3-(1-adamantyl)-4-hydroxybenzoic acid and 5.31 g (38.4 mmoles) ofpotassium carbonate in 100 ml of DMF, there are slowly added 12.0 g(41.9 mmoles) of 2,2-dimethyl-1,3-dioxolane-4-methyltosylate in 75 ml ofDMF. The mixture is stirred at 100° C. for 12 hours. The reaction mediumis poured into ice water and extracted with 900 ml of ether. The organicphase is washed with water, dried on magnesium sulfate and evaporated.The resulting residue is chromatographed on silica by eluting with an80:20 mixture of hexane and ethyl acetate which yields after evaporationof the solvents 8.82 g (63% yield) of methyl3-(1-adamantyl)-4-(2,2-dimethyl-1,3-dioxolane-4-methyloxy) benzoatehaving a melting point of 159° C.

(b) 3-(1-adamantyl)-4-(2,2-dimethyl-1,3-dioxolane-4-methyloxy) benzoicacid

To a solution of 8.80 g 22 mmoles) of methyl3-(1-adamantyl)-4-(2,2-dimethyl-1,3-dioxolane-4-methyloxy) benzoate in200 ml of methanol, there are added 16 g (0.4 mole) of soda. The mixtureis heated at reflux for 3 1/2 hours. The reaction medium is evaporatedand the residue is taken up in 250 ml of water, then acidified to pH 3.The precipitate is extracted with 1.4 liters of ethyl ether. The organicphase is washed with water, dried on magnesium sulfate and evaporated.After pulverizing in hexane, 8.32 g (98% yield) of3-(1-adamantyl)-4-(2,2-dimethyl-1,3-dioxolane-4-methyloxy) benzoic acidhaving a melting point of 224°-225° C. are isolated.

(c) allyl 4-[3-(1-adamantyl)-4-(2,2-dimethyl-1,3-dioxolane-4-methyloxy)benzoyloxy] benzoate

To a solution of 4.15 g (10.75 mmoles) of3-(1-adamantyl)-4-(2,2-dimethyl-1,3-dioxolane-4-methyloxy) benzoic acidin 40 ml of dichloromethane, there are added 2.15 ml ofdicyclohexylamine (10.8 mmoles) and the reaction is permitted to proceedfor 1 hour at ambient temperature. There is then slowly added 0.85 ml(11.8 mmoles) of thionyl chloride. After stirring at ambient temperaturefor 4 hours, the medium is evaporated to dryness, and the residue istaken up in ethyl ether. The insolubles are removed by filtration andthe filtrate is evaporated. The3-(1-adamantyl)-4-(2,2-dimethyl-1,3-dioxolane-4-methyloxy) benzoic acidthus obtained is placed in 30 ml of THF to which is then slowly added asolution, with stirring, containing 1.91 g (10.7 mmoles) of allyl4-hydroxybenzoate, 1.65 ml (11.8 mmoles) of triethylamine and 13 mg ofdimethylaminopyridine in 30 ml of THF. The reaction medium is stirred atambient temperature under nitrogen for 20 hours and is then poured intoice water. This suspension is extracted with 600 ml of ethyl ether. Theorganic phase is then dried and evaporated. The residue ischromatographed on silica by eluting with dichloromethane to yield 4.24g (72% yield) of allyl 4-[3-(1-adamantyl)-4- 2,2-dimethyl-1,3-dioxolane-4-methyloxy) benzoyloxy] benzoate having amelting point of 106°-107° C.

(d) allyl 4-[3-(1-adamantyl)-4-(2,3-dihydroxypropyloxy) benzoyloxybenzoate

1.09 g (2 mmoles) of allyl4-[3-(1-adamantyl)-4-(2,2-dimethyl-1,3-dioxolane-4-methyloxy)benzoyloxy] benzoate are placed in 50 ml of dichloromethane and 3.80 g(20 mmoles) of paratoluene sulfonic acid are added. The reaction is leftto proceed, with stirring, for 48 hours at ambient temperature. Themedium is evaporated to dryness and the residue is taken up in 50 ml ofdichloromethane. The organic phase is neutralized by washing withsaturated NaHCO₃, then rinsed with water, dried and evaporated. Theresidue is chromatographed on silica eluting with a 90:10 mixture ofdichloromethane and ethyl ether thereby yielding 900 mg (89% yield) ofallyl 4-[3-(1-adamantyl)-4-(2,3-dihydroxypropyloxy) benzoyloxy]benzoate.

(e) 4-[3-(1-adamantyl)-4-(2,3-dihydroxypropyloxy) benzoyloxy] benzoicacid

To a solution of 891 mg (1.76 mmoles) of allyl4-[3-(1-adamantyl)-4-(2,3-dihydroxypropyloxy) benzoyloxy] benzoate in 15ml of THF, there are added 102 mg (0.088 mmole) of tetrakis(triphenylphosphine) palladium (O). There is then slowly introduced asuspension consisting of 58 mg (1.93 mmoles) of sodium hydride (80% inoil) and 294 μl (1.93 mmoles) of ethyl malonate in 6 ml of THF. Themixture is stirred under nitrogen at ambient temperature for 1 hour andthen evaporated to dryness. The solid is washed with 50 ml of ether,placed in 50 ml of water, acidified to pH 1 and extracted with 100 ml ofether. The organic phase is rinsed with water, dried on sodium sulfateand evaporated. The residue is recrystallized in ethyl acetate yielding634 mg (72% yield) of 4-[3-(1-adamantyl)-4-(2,3-dihydroxypropyloxy)benzoyloxy] benzoic acid having a melting point of 238°-239° C.

EXAMPLE 28 4-[3-(1-adamantyl)-4-methoxycarbonylmethyloxy] benzoic acid(a benzyl 4-[3-(1-adamantyl)-4-tert.butyldimethylsilyloxybenzoyloxy]benzoate

38.66 g (0.1 mole) of 3-(1-adamantyl)-4-tert.butyldimethylsilyloxybenzoic acid are converted to the acid chloride by the method previouslydescribed, then dissolved in 140 ml of THF and slowly added to asuspension containing 1.66 g (0.055 mmoles) of NaH (80% in oil) and 1.41g (0.05 mole) of benzyl 4-hydroxybenzoate in 5 ml of THF. Thetemperature is permitted to return to ambient temperature with stirringfor 24 hours. The reaction medium is poured into ice water and extractedwith ethyl ether. The organic phase is washed with water, dried onmagnesium sulfate and evaporated. The residue is chromatographed onsilica, eluting with a 40:60 mixture of dichloromethane and hexaneyielding 28 g (47% yield) of benzyl4-[3-(1-adamantyl)-4-tert.butyldimethylsilyloxy] benzoate having amelting point of 151°-152° C.

(b) benzyl 4-[3-(1-adamantyl)-4-hydroxybenzoyloxy] benzoate

A solution of 5.7 g (9.55 mmoles) of benzyl4-[3-(1-adamantyl)-4-tert.butyldimethylsilyloxybenzoyloxy] benzoate in35 ml of THF is treated with 10.5 ml of tetrabutylammonium fluoride in1M THF. The reaction medium is stirred at ambient temperature for 1 hourand then poured into ice water and extracted with 700 ml of ethyl ether.The organic phase is washed with 1N HCl, rinsed with water, dried onmagnesium sulfate and evaporated. 4.60 g (100% yield) of benzyl4-[3-(1-adamantyl)-4-hydroxybenzoyloxy] benzoate having a melting pointof 164°-165° C. are isolated.

(c) benzyl 4-[3-(1-adamantyl)-4-methoxycarbonylmethyloxy] benzoate

1.0 ml (10.2 mmoles) of methyl bromoacetate is slowly added to asolution of 4.49 g (9.3 mmoles) of benzyl4-[3-(1-adamantyl)-4-hydroxybenzoyloxy] benzoate in 40 ml of DMFcontaining 309 mg (10.2 mmoles) of NaH (80% in oil). The reaction mediumis left, with stirring, at ambient temperature overnight and then pouredinto ice water and extracted with 550 ml of ethyl ether. The organicphase is washed with water, dried on magnesium sulfate and evaporated.After chromatography on silica eluted with a 90:10 mixture ofdichloromethane, 3.50 g (68% yield) of benzyl4-[3-(1-adamantyl)-4-methoxycarbonylmethyloxy] benzoate having a meltingpoint of 123°-124° C. are isolated. (d)4-[3-(1-adamantyl)-4-methoxycarbonylmethyloxy] benzoic acid 3.46 g (6.24mmoles) of benzyl 4-[3-(1-adamantyl)-4-methoxycarbonylmethyloxy]benzoate in 50 ml of dioxan are hydrogenated under a pressure of 7 barsin the presence of 346 mg of Pd-C (10%) for 2 hours at 40° C. Thereaction medium is filtered on kelite and evaporated, thereby yieldingafter recrystallization in ethyl acetate 2.55 g (88% yield) of4-[3-(1-adamantyl)-4-methoxycarbonylmethyloxy] benzoic acid having amelting point of 252°-253° C.

EXAMPLES OF COMPOSITION A - Oral compositions

    ______________________________________                                        (a) 0.2 g tablet                                                              4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-                                                              0.001    g                                            3-fluorobenzoic acid                                                          Starch                  0.114    g                                            Dicalcium phosphate     0.020    g                                            Silica                  0.020    g                                            Lactose                 0.030    g                                            Talc                    0.010    g                                            Magnesium stearate      0.005    g                                            (b) Drinkable suspension in 5 ml ampoule                                      4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-                                                              0.001    g                                            2-fluorobenzoic acid                                                          Glycerine               0.500    g                                            Sorbitol, 70%           0.500    g                                            Sodium saccharinate     0.010    g                                            Methyl parahydroxybenzoate                                                                            0.040    g                                            Flavoring agent, sufficient amount                                            Purified water, sufficient amount for                                                                 5        ml                                           (c) 0.8 g tablet                                                              4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-                                                              0.500    g                                            2-hydroxybenzoic acid                                                         Pregelatinized starch   0.100    g                                            Microcrystalline cellulose                                                                            0.115    g                                            Lactose                 0.075    g                                            Magnesium stearate      0.010    g                                            ______________________________________                                    

In Example (c), 4-[3-(1-adamantyl)-4-methoxybenzoyloxy[-2-hydroxybenzoicacid can be replaced by 4-[5-(1-adamantyl)-2-fluoro-4-methoxybenzoyloxy]benzoic acid.

    ______________________________________                                        (d) Drinkable suspension in 10 ml ampoule                                     4-(3,5-di-tert.butyl-4-hydroxybenzoyloxy)                                                              0.200    g                                           benzoic acid                                                                  Glycerine                1.000    g                                           Sorbitol, 70%            1.000    g                                           Sodium saccharinate      0.010    g                                           Methyl parahydroxybenzoate                                                                             0.080    g                                           Flavoring agent, sufficient amount                                            Purified water, sufficient amount for                                                                  10       ml                                          B. Topical Compositions                                                       (a) Salve                                                                     4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-                                                               0.020    g                                           3-fluorobenzoic acid                                                          Isopropyl myristate      81.700   g                                           Fluid petrolatum oil     9.100    g                                           Silica, sold under the trade name                                                                      9.180    g                                           "AEROSIL 200" be Degussa                                                      (b) Salve                                                                     4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-                                                               0.300    g                                           2-fluorobenzoic acid                                                          Codex white petrolatum, sufficient                                                                     100      g                                           amount for                                                                    (c) Nonionic water-in-oil cream                                               4-(3,5-di-tert.butyl-4-hydroxybenzoyloxy)                                                              0.100    g                                           benzoic acid                                                                  Anhydrous eucerin        39.900   g                                           Methyl parahydroxybenzoate                                                                             0.075    g                                           Propyl parahydroxybenzoate                                                                             0.075    g                                           Sterile demineralized water, sufficient                                                                100      g                                           amount for                                                                    (d) Lotion                                                                    4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-                                                               0.100    g                                           2-hydroxybenzoic acid                                                         PEG 400                  69.900   g                                           Ethanol, 95%             30.000   g                                           (e) Hydrophobic salve                                                         4-[5-(1-adamantyl)-2-fluoro-4-                                                                         0.300    g                                           methoxybenzoyloxy] benzoic acid                                               Isopropyl myristate      36.400   g                                           Silicone oil, sold by Rhone Poulenc                                                                    36.400   g                                           under the trade name "Rhodorsil                                               47 V 300"                                                                     Beeswax                  13.600   g                                           Silicone oil, sold by Goldschmidt under                                                                100      g                                           the trade name "Abil 300.000cst" ,                                            sufficient amount for                                                         (f) Nonionic oil-in-water cream                                               4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-                                                               1.000    g                                           3-fluorobenzoic acid                                                          Cetyl alcohol            4.000    g                                           Glycerol monostearate    2.500    g                                           PEG 50 stearate          2.500    g                                           Karite butter            9.200    g                                           Propylene glycol         2.000    g                                           Methyl parahydroxybenzoate                                                                             0.075    g                                           Propyl parahydroxybenzoate                                                                             0.075    g                                           Sterile demineralized water,                                                                           100      g                                           sufficient amount for                                                         C. Administration by injection                                                3 ml injectable ampoule                                                       4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-                                                               0.003    g                                           2-hydroxy benzoic acid, micronized                                            Water for injectable preparation,                                                                      3        ml                                          sufficient amount for                                                         ______________________________________                                    

What is claimed is:
 1. A bi-aromatic ester having the formula ##STR13##wherein R₁ represents --COOR₉,R₉ represents hydrogen, alkyl having 1-6carbon atoms, monohydroxyalkyl or polyhydroxyalkyl, R₂ representshydrogen, alkyl having 1-6 carbon atoms, OR₉, fluorine or --CF₃, R₃, R₄and R₅ represent hydrogen, fluorine, OH, --CH₃, --OCH₃, --CF₃, --COOH or--CH₂ OH, R₆ and R₈, each independently, represent hydrogen, substitutedalkyl having 3-15 carbon atoms and 1-adamantyl, R₇ represents hydrogen,alkyl having 1-6 carbon atoms, alkenyl and OR₁₂ wherein R₁₂ representshydrogen, alkyl having 1-6 carbon atoms and alkenyl, with the provisothat when R₂ represents hydrogen, then:(i) either R₃ and R₄ are otherthan hydrogen or --CH₃, (ii) or R₇ is other than OR₁₂ and R₆ or R₈ is1-adamantyl, (iii) or R₇ represents OR₁₂, but R₆ and R₈ are other thanhydrogen, and (iv) or R₇ represents OR₁₂ but R₅ is other than hydrogen.2. The compound of claim 1 is the form of an alkali metal salt, analkaline earth metal salt, a zinc salt or an organic amine salt.
 3. Thecompound of claim 1 wherein said alkyl having 1-6 carbon atoms isselected from the group consisting of methyl, ethyl, isopropyl, butyland tert.butyl.
 4. The compound of claim 1 wherein said substitutedalkyl is selected from the group consisting of 1-methyl propyl, 1-ethylpropyl, 1-methyl hexyl, 1-methyl decyl or 1-ethyl dodecyl.
 5. Thecompound of claim 1 wherein said substituted alkyl is selected from thegroup consisting of tert.butyl, 1,1-dimethyl propyl, 1-methyl-1-ethylpropyl, 1-methyl-1-ethyl hexyl and 1,1-dimethyl decyl.
 6. The compoundof claim 1 wherein said monohydroxyalkyl is 2-hydroxyethyl,2-hydroxypropyl or 3-hydroxypropyl.
 7. The compound of claim 1 whereinsaid polyhydroxyalkyl has 3-6 carbon atoms and 2-5 hydroxyl groups. 8.The compound of claim 7 wherein said polyhydroxyalkyl is2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentylor the residue of pentaerythritol.
 9. The compound of claim 1 whereinsaid alkenyl having 2-6 carbon atoms is vinyl, allyl or 2-butenyl. 10.The compound of claim 1 selected from the group consistingof4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-3-fluorobenzoic acid,4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-fluorobenzoic acid,4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-methylbenzoic acid,4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-hydroxybenzoic acid,4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-methoxybenzoic acid,4-[3-(1-adamantyl)-4 -methoxybenzoyloxy]-3-methoxybenzoic acid,4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-trifluoromethylbenzoic acid,methyl 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-hydroxybenzoate,4-[5-(1-adamantyl)-2-fluoro-4-methoxybenzoyloxy] benzoic acid,4-[5-(1-adamantyl)-2,4-dimethoxybenzoyloxy] benzoic acid,4-[3-(1-adamantyl) benzoyloxy] benzoic acid,4-(3,5-di.tert-butyl-4-hydroxybenzoyloxy) benzoic acid,4-[3-(1-adamantyl)-4-vinylbenzoyloxy] benzoic acid,4-[3-(1-adamantyl)-4-ethylbenzoyloxy] benzoic acid,4-[3-(1-adamantyl)-4-butylbenzoyloxy] benzoic acid,4-[3-(1-adamantyl)-4-allyloxybenzoyloxy] benzoic acid,4-[3-(1-adamantyl)-4-methoxybenzoyloxy] isophthalic acid, and4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-3-hydroxymethyl benzoic acid.11. The compound of claim 1 having the formula ##STR14## wherein (i)either R₃ to R₉ have the meanings given in claim 1, and R₂ representsalkyl having 1-6 carbon atoms, OR₉, fluorine or --CF₃,(ii) or R₂ to R₄and R₆ to R₉ have the meanings given in claim 1 and R₅ representsfluorine.
 12. A pharmaceutical composition comprising in apharmaceutically acceptable vehicle suitable for enteral, parenteral,topical or ocular administration to an animal or man, at least onecompound of formula (I) of claim
 1. 13. The composition of claim 12Wherein said compound of formula (I) is present in an amount rangingfrom 0.0001 to about 5 percent by weight based on the total weight ofsaid composition.
 14. A method for the treatment of a dermatologic,rheumatismal, respiratory or ophthalomolgic ailment comprisingadministering to an animal or a person suffering from said ailment aneffective amount of the composition of claim
 12. 15. A cosmeticcomposition for body and hair hygiene comprising in a cosmeticallyacceptable/ vehicle at least one compound of formula (I) of claim
 1. 16.The composition of claim 15 wherein said compound of formula (I) ispresent in an amount ranging from 0.0001 to 1 percent by weight based onthe total weight of said composition.
 17. The composition of claim 15wherein said compound of formula (I) is present in an amount rangingfrom 0.001 to 0.01 percent by weight based on the total weight of saidcomposition.